CD28 and inducible costimulatory protein Src homology 2 binding domains show distinct regulation of phosphatidylinositol 3-kinase, Bcl-xL, and IL-2 expression in primary human CD4 T lymphocytes
CD28 and inducible costimulatory protein Src homology 2 binding domains show distinct regulation of phosphatidylinositol 3-kinase, Bcl-xL, and IL-2 expression in primary human CD4 T lymphocytes
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DOI：
10.4049/jimmunol.171.1.166
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发表时间：
2003-07-01
影响因子：
4.4
通讯作者：
Riley, JL
中科院分区：
文献类型：
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作者：
Parry, RV;Rumbley, CA;Riley, JL
CD28或可诱导共刺激蛋白(ICOS)的连接产生了最佳T细胞激活和增殖所需的第二信号。ICOS和CD28共刺激T细胞的一个显著区别是产生IL-2的数量不同。为了理解为什么CD28而不是ICOS引起IL-2表达的显著增加，我们比较了这些分子激活与IL-2调节有关的信号转导级联的能力。在磷脂酰肌醇3-激酶活性(PI3K)和e-jun氨基末端激酶的调节方面存在重大差异。与CD28共刺激相比，ICOS共刺激导致PI3K活性显著增强，而只有CD28共刺激激活c-jun氨基末端激酶。为了研究这些信号转导的差异如何影响IL-2的产生，我们用慢病毒载体转导原代人CD4T细胞，该载体表达带有各种人CD28和ICOS胞质结构域的小鼠CD28胞外区。这些结构域能够作为离散的信号单元运行，这表明它们可以独立发挥作用。我们的结果表明，尽管ICOS Src Homology(SH)2结合域强烈激活PI3K，但它不能替代CD28SR2结合域诱导高水平的IL-2和Bclx(L)。此外，CD28SH2结合区本身就足以调节BCI-x(L)的最佳诱导水平，而整个CD28细胞质尾部是高水平表达IL-2所必需的。因此，它们各自SH2结合区的不同至少部分解释了ICOS或CD28介导的共刺激对IL-2和Bclx(L)表达的不同调控。
Ligation of either CD28 or inducible costimulatory protein (ICOS) produces a second signal required for optimal T cell activation and proliferation. One prominent difference between ICOS- and CD28-costimulated T cells is the quantity of IL-2 produced. To understand why CD28 but not ICOS elicits major increases in IL-2 expression, we compared the abilities of these molecules to activate the signal transduction cascades implicated in the regulation of IL-2. Major differences were found in the regulation of phosphatidylinositol 3-kinase activity (PI3K) and e-jun N-terminal kinase. ICOS costimulation led to greatly augmented levels of PI3K activity compared with CD28 costimulation, whereas only CD28 costimulation activated c-jun N-terminal kinase. To examine how these differences in signal transduction affected IL-2 production, we transduced primary human CD4 T cells with a lentiviral vector that expressed the murine CD28 extracellular domain with a variety of human CD28 and ICOS cytoplasmic domain swap constructs. These domains were able to operate as discrete signaling units, suggesting that they can function independently. Our results show that even though the ICOS Src homology (SH) 2 binding domain strongly activated PI3K, it was unable to substitute for the CD28 SR2 binding domain to induce high levels of IL-2 and Bcl-x(L). Moreover, the CD28 SH2 binding domain alone was sufficient to mediate optimal levels of BcI-x(L) induction, whereas the entire CD28 cytoplasmic tail was required for high levels of IL-2 expression. Thus, differences within their respective SH2 binding domains explain, at least in part, the distinct regulation of IL-2 and Bcl-x(L) expression following ICOS- or CD28-mediated costimulation.